The production of genomic data for the All of Us Research Program (AoU) is an unprecedented opportunity to support a comprehensive precision medicine effort that benefits the entire U.S. population. With the participation from patients, family members, researchers and clinicians, this opportunity will impact clinical management by directing patient care, enabling pre-symptomatic genetic testing of relatives, guiding familyplanning measures, and triggering healthcare interventions. We propose to create the HudsonAlpha Consortium for Population Genomics (HACPG) for AoU as a platform for high quality microarray, sequence, and clinical interpretation of high-value variants. The HACPG will leverage the experience and breadth of our clinical team and consortium members to allow accurate and cost-effective production of annotated variant data from the largest number of cases and samples possible. The data we generate will be formatted and transferred to the program Data Resource Center (DRC) to facilitate return of clinical results to the Genetic Counseling Resource as directed by the program. Our overarching strategy in developing this proposal is to combine best-in-field teams to form a consortium dedicated to enabling scalable genomics in an evolvable platform. This platform will easily support advancements in the genomics field, efficiently combining existing technical and analytic resources. Our efforts will facilitate a path to move unbiased genetic testing such as whole-genome sequencing to routine use in healthcare and lifestyle management. The roles and relationships of HACPG consortium members are summarized below (Fig 1.1). HACPG is a collaboration between HudsonAlpha Institute for Biotechnology (lead institution, sequencing, and clinical validation laboratory), Rutgers University (sample intake, quality control and genotyping), University of Utah (data analysis), Fabric Genomics (clinical reporting) and Helix (return of results and value add). With the significant expansion of sequencing volume in years 2-5 of AoU, the HACPG will expand to include Baylor College of Medicine Human Genome Sequencing Center Clinical Lab (HGSC-CL) to provide a known and trusted partner to expand the capacity of the consortium to support the requested volumes (see Letters of Support 7.4 to 7.6 in Section 7). As lead institution, HudsonAlpha Institute for Biotechnology benefits from a unique background. HudsonAlpha was founded ten years ago with a mission to improve genomic literacy and support the application of genomic technologies in education, research, healthcare and economic development. Since its founding, HudsonAlpha has grown significantly in each of its mission areas and has made significant contributions to the genomics field. Some key highlights and unique accomplishments with references to the relevant sections of our proposal are: ? HudsonAlpha established the first CAP-accredited, CLIA licensed lab offering whole-genome sequencing (WGS) and currently has capacity for sequencing over 70,000 clinical genomes per year (please see Section 2.C.1). ? HudsonAlpha has generated ~30X+ genomes from thousands of individuals and returned definitive diagnoses for hundreds of patients through our UDN and CSER programs (please see Section 3). ? HudsonAlpha is co-leading the Alabama Genomics Health Initiative; a program that mirrors many of the features of AoU and has provided vital early perspectives on population scale programs that utilize multiple technologies (please see Section 3). ? Although HudsonAlpha has resources to support the full AoU scope of work, we have made strategic partnerships to provide the best available options and flexibility to AoU, especially in the later years of the program (please see this section and Figure 1.1). ? HudsonAlpha has production-scale experience with the Illumina NovaSeq 6000 demonstrated by more than 25,000 whole-genomes or equivalents in the first half of 2018 (please see Section 2.C). ? We have developed a highly optimized library and sequencing platform that has proven scalability, performance and integrity (please see Section 2.C.1). ? To match our sequencing production capabilities we have developed a scalable data analysis and storage platform that is in production and fully validated (please see Section 2.C.2). ? We have develop an innovative interpretation and return of results strategy that has opportunities for strong scalability and development should the AoU program expand and pursue direct-to-consumer return for non-clinical variants (please see Section 3.D). ? We have presented an innovative validation strategy to leverage long-read sequencing technologies to offer a cost and accuracy not possible with Sanger (please see Section 2.D.).